Suppression of Pathological Spontaneous Cortical Dynamics and Inflammation in NeuroHIV

NeuroHIV 病理性自发皮质动力学和炎症的抑制

• 批准号: 10472343
• 负责人: Tony W Wilson
• 金额: $ 68.87万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472343
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Agreement; Anti-Inflammatory Agents; Area; Attention; Automobile Driving; Behavior; Behavioral; Brain; Brain Mapping; Brain region; Cannabinoids; Cannabis; Chronic; Cognitive; Complication; Data Analyses; Disease; Economics; Environment; Epidemic; Equation; Exhibits; Foundations; Functional disorder; General Population; Goals; HIV; HIV Infections; Heel; Human; Immune; Impaired cognition; Impairment; Inflammation; Knowledge; Lead; Life Expectancy; Link; Mediating; Methods; Mitochondria; Modeling; Molecular; Motor; Neurologic; Neurophysiology - biologic function; Neuropsychological Tests; Oxidation-Reduction; Participant; Pathologic; Pathway interactions; Performance; Persons; Property; Publishing; Quality of life; Reporting; Request for Proposals; Research; Risk; Sampling; Scientific Advances and Accomplishments; Seminal; Superoxides; System; Systems Biology; Targeted Research; Task Performances; Therapeutic; Unemployment; Viral; Western World; Work; cognitive function; cognitive performance; comorbidity; immune activation; improved; innovation; instrumentation; marijuana use; medication compliance; mild cognitive impairment; molecular marker; nervous system disorder; neuroAIDS; neuroimaging; neuroimaging marker; neuroinflammation; relating to nervous system; virtual

Project Summary/Abstract Persons with HIV (PWH) in the western world have a life expectancy near that of the general population, yet they remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Recent human neuroimaging studies have broadly shown that the milder impairments more frequently observed in virally-suppressed PWH arise from multiple cortical circuits, which is a major paradigm shift from the putative subcortical origins of the severe cognitive impairments observed earlier in the epidemic. However, despite this progress, we still have a limited understanding of the molecular precursors and pathways that lead to dysfunction in these cortical circuits, and virtually no viable therapeutic options, with only limited potential avenues (e.g., cannabis) on the horizon. This proposal responds to RFA-DA-22-012, which calls for applications that “define HIV-associated persistent inflammation and its causal link to HIV-related comorbidities such as … neurological disorders,” “explore the interaction between HIV immune activation and cannabinoid use as it pertains to neurological disorders,” and “characterize and validate the potential anti-inflammatory, immune stabilizing (beneficial) properties of canna- binoids in chronic HIV infection.” The proposed project responds to this call with an innovative, large-scale, dynamic neuroimaging and molecular markers study that leverages multiple recent discoveries to identify the impact of cannabis use on the mechanisms and pathways underlying HIV-related persistent inflammation and decline in cognitive and brain function in virally-suppressed PWH. Each of our aims builds on a major discovery in 2021. Specifically, Aim 1 examines whether cannabis use modulates the superoxide-sensitive mitochondrial redox environment and neuroinflammation in PWH, which follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH compared to controls, and that the latter predicts neuro- inflammation and cognitive function. Aim 2 identifies whether attention- and motor-related neural oscillations are directly modulated by the same superoxide-sensitive pathway in PWH, which builds on our major discovery featured in PNAS that the superoxide-sensitive mitochondrial redox environment predicts cognitive performance and the underlying neural oscillations in controls. Finally, Aim 3 builds on our recent breakthrough that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and further accentuated in cognitively impaired PWH, by examining whether these cannabis-induced alterations are mediated by the superoxide-sensitive mitochondrial redox environment. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that utilizes state-of- the-art neuroimaging and systems biology methods, and builds on an established model of neuroinflammation in PWH that has been linked to cognitive and neural function in healthy adults and cognitive decline in PWH.

项目概要/摘要 西方世界艾滋病毒感染者 (PWH) 的预期寿命接近普通人群，但 他们发生认知障碍的风险仍然显着升高。此类损伤是最 HIV 疾病常见的神经系统并发症，针对这些合并症的研究是四个 艾滋病研究办公室确定的总体优先事项 (NOT-OD-20-018)。最近的人类神经影像学 研究广泛表明，在病毒抑制的感染者中更容易观察到较轻微的损伤 由多个皮质回路产生，这是相对于假定的皮质下起源的一个重大范式转变 疫情早期观察到的严重认知障碍。然而，尽管取得了这些进展，我们仍然有 对导致这些皮质回路功能障碍的分子前体和途径的了解有限， 几乎没有可行的治疗选择，只有有限的潜在途径（例如大麻）。 该提案是对 RFA-DA-22-012 的回应，该提案呼吁“定义与 HIV 相关的持久性 炎症及其与 HIV 相关合并症（例如……神经系统疾病）的因果关系”，“探索 HIV 免疫激活和大麻素使用之间的相互作用，因为它与神经系统疾病有关，”和 “表征并验证大麻的潜在抗炎、免疫稳定（有益）特性 慢性艾滋病毒感染中的二元生物。”拟议的项目以创新的、大规模的、 动态神经影像和分子标记研究，利用多项最新发现来识别 大麻使用对艾滋病毒相关持续性炎症机制和途径的影响 病毒抑制的感染者的认知和大脑功能下降。我们的每一个目标都建立在重大发现的基础上 2021 年。具体来说，目标 1 检查大麻的使用是否会调节超氧化物敏感的线粒体 氧化还原环境和 PWH 中的神经炎症，紧接着我们发现线粒体 与对照组相比，PWH 中的功能差异调节超氧化物，并且后者预测神经- 炎症和认知功能。目标 2 确定是否存在与注意力和运动相关的神经振荡 直接受到 PWH 中相同的超氧化物敏感途径的调节，这是基于我们的重大发现 PNAS 报道超氧化物敏感线粒体氧化还原环境可预测认知表现 以及控制中潜在的神经振荡。最后，Aim 3 建立在我们最近的突破基础上，即大麻 抑制在 PWH 中观察到的病理性自发皮质活动，并在 认知受损的 PWH，通过检查这些大麻引起的改变是否是由 超氧化物敏感的线粒体氧化还原环境。这些最近的重大科学进展提供了理想的 基金会通过利用现状的创新项目直接解决本 RFA 的关键目标 最先进的神经影像和系统生物学方法，并建立在已建立的神经炎症模型的基础上 与健康成年人的认知和神经功能以及感染者认知能力下降有关。